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Velcade 3.5 Mg 1 Vial

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

1.1 Multiple Myeloma

1.2 Mantle Cell Lymphoma

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Guidelines

2.2 Dosage in Previously Untreated Multiple Myeloma

2.3 Dose Modification Guidelines for VELCADE When Given in Combination with Melphalan and Prednisone

2.4 Dosage and Dose Modifications for Relapsed Multiple Myeloma and Mantle Cell Lymphoma

2.5 Dose Modifications for Peripheral Neuropathy

2.6 Dosage in Patients with Hepatic Impairment

2.7 Administration Precautions

2.8 Reconstitution/Preparation for Intravenous and Subcutaneous Administration

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Peripheral Neuropathy

5.2 Hypotension

5.3 Cardiac Toxicity

5.4 Pulmonary Toxicity

5.5 Posterior Reversible Encephalopathy Syndrome (PRES)

5.6 Gastrointestinal Toxicity

5.7 Thrombocytopenia/Neutropenia

5.8 Tumor Lysis Syndrome

5.9 Hepatic Toxicity

5.10 Embryo-fetal Risk

6 ADVERSE REACTIONS

6.1 Clinical Trials Safety Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 CYP3A4 inhibitors

7.2 CYP2C19 inhibitors

7.3 CYP3A4 inducers

7.4 Dexamethasone

7.5 Melphalan-Prednisone

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Patients with Renal Impairment

8.7 Patients with Hepatic Impairment

8.8 Patients with Diabetes

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

14.1 Multiple Myeloma

14.2 Mantle Cell Lymphoma

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

*Sections or subsections omitted from the full prescribing information are not listed.

 

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Multiple Myeloma

VELCADE® (bortezomib) is indicated for the treatment of patients with multiple myeloma.

1.2 Mantle Cell Lymphoma

VELCADE is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Guidelines

The recommended starting dose of VELCADE is 1.3 mg/m2. VELCADE may be administered intravenously at a concentration of 1 mg/mL, or subcutaneously at a concentration of 2.5 mg/mL [see Dosage and Administration (2.8)].

VELCADE retreatment may be considered for patients with multiple myeloma who had previously responded to treatment with VELCADE and who have relapsed at least 6 months after completing prior VELCADE treatment. Treatment may be started at the last tolerated dose [see Dosage and Administration (2.4)].

When administered intravenously, VELCADE is administered as a 3 to 5 second bolus intravenous injection. VELCADE is for intravenous or subcutaneous use only. VELCADE should not be administered by any other route.

Because each route of administration has a different reconstituted concentration, caution should be used when calculating the volume to be administered.

2.2 Dosage in Previously Untreated Multiple Myeloma

VELCADE is administered in combination with oral melphalan and oral prednisone for nine 6-week treatment cycles as shown in Table 1. In Cycles 1-4, VELCADE is administered twice weekly (days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5-9, VELCADE is administered once weekly (days 1, 8, 22 and 29). At least 72 hours should elapse between consecutive doses of VELCADE.

Table 1: Dosage Regimen for Patients with Previously Untreated Multiple Myeloma

Twice Weekly VELCADE (Cycles 1-4)

Week

1

2

3

4

5

6

VELCADE
(1.3 mg/m2)

Day
1

--

--

Day
4

Day
8

Day
11

rest
period

Day
22

Day
25

Day
29

Day
32

rest
period

Melphalan(9 mg/m2)
Prednisone(60 mg/m2)

Day
1

Day
2

Day
3

Day
4

--

--

rest
period

--

--

--

--

rest
period

Once Weekly VELCADE (Cycles 5-9 when used in combination with Melphalan and Prednisone)

Week

1

2

3

4

5

6

VELCADE
(1.3 mg/m2)

Day
1

--

--

 

Day
8

 

rest
period

Day
22

 

Day
29

 

rest
period

Melphalan(9 mg/m2)
Prednisone(60 mg/m2)

Day
1

Day
2

Day
3

Day
4

--

--

rest
period

--

--

--

--

rest
period

2.3 Dose Modification Guidelines for VELCADE When Given in Combination with Melphalan and Prednisone

Prior to initiating any cycle of therapy with VELCADE in combination with melphalan and prednisone:

  • Platelet count should be at least 70 × 109/L and the absolute neutrophil count (ANC) should be at least 1.0 × 109/L
  • Non-hematological toxicities should have resolved to Grade 1 or baseline

Table 2: Dose Modifications during Cycles of Combination VELCADE, Melphalan and Prednisone Therapy

Toxicity

 

Dose modification or delay

For information concerning melphalan and prednisone, see manufacturer's prescribing information.

Hematological toxicity during a cycle:
If prolonged Grade 4 neutropenia or thrombocytopenia, or thrombocytopenia with bleeding is observed in the previous cycle

 

Consider reduction of the melphalan dose by 25% in the next cycle

If platelet count is not above 30 × 109/L or ANC is not above 0.75 × 109/L on a VELCADE dosing day (other than day 1)

 

Withhold VELCADE dose

If several VELCADE doses in consecutive cycles are withheld due to toxicity

 

Reduce VELCADE dose by 1 dose level (from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2)

Grade 3 or higher non-hematological toxicities

 

Withhold VELCADE therapy until symptoms of toxicity have resolved to Grade 1 or baseline. Then, VELCADE may be reinitiated with one dose level reduction (from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2). For VELCADE-related neuropathic pain and/or peripheral neuropathy, hold or modify VELCADE as outlined in Table 3.

Dose modifications guidelines for peripheral neuropathy are provided [see Dosage and Administration (2.5)].

2.4 Dosage and Dose Modifications for Relapsed Multiple Myeloma and Mantle Cell Lymphoma

VELCADE (1.3 mg/m2/dose) is administered twice weekly for 2 weeks (Days 1, 4, 8, and 11) followed by a 10-day rest period (Days 12-21). For extended therapy of more than 8 cycles, VELCADE may be administered on the standard schedule or on a maintenance schedule of once weekly for 4 weeks (Days 1, 8, 15, and 22) followed by a 13-day rest period (Days 23 to 35) [see Clinical Studies (14)]. At least 72 hours should elapse between consecutive doses of VELCADE.

Patients with multiple myeloma who have previously responded to treatment with VELCADE (either alone or in combination) and who have relapsed at least 6 months after their prior VELCADE therapy may be started on VELCADE at the last tolerated dose. Retreated patients are administered VELCADE twice weekly (Days 1, 4, 8, and 11) every three weeks for a maximum of 8 cycles. At least 72 hours should elapse between consecutive doses of VELCADE. VELCADE may be administered either as a single agent or in combination with dexamethasone [see Clinical Studies (14.1)].

VELCADE therapy should be withheld at the onset of any Grade 3 non-hematological or Grade 4 hematological toxicities excluding neuropathy as discussed below [see Warnings and Precautions (5)]. Once the symptoms of the toxicity have resolved, VELCADE therapy may be reinitiated at a 25% reduced dose (1.3 mg/m2/dose reduced to 1 mg/m2/dose; 1 mg/m2/dose reduced to 0.7 mg/m2/dose).

For dose modifications guidelines for peripheral neuropathy see Management of Peripheral Neuropathy section (2.5).

2.5 Dose Modifications for Peripheral Neuropathy

Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy. Patients with pre-existing severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment.

Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may require a decrease in the dose and/or a less dose-intense schedule.

For dose or schedule modification guidelines for patients who experience VELCADE-related neuropathic pain and/or peripheral neuropathy see Table 3.

Table 3: Recommended Dose Modification for VELCADE related Neuropathic Pain and/or Peripheral Sensory or Motor Neuropathy

Severity of Peripheral Neuropathy Signs and Symptoms*

 

Modification of Dose and Regimen

* Grading based on NCI Common Terminology Criteria CTCAE v4.0

† Instrumental ADL: refers to preparing meals, shopping for groceries or clothes, using telephone, managing money etc;

‡ Self care ADL: refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden

Grade 1 (asymptomatic; loss of deep tendon reflexes or paresthesia) without pain or loss of function

 

No action

Grade 1 with pain or Grade 2 (moderate symptoms; limiting instrumental Activities of Daily Living (ADL)†)

 

Reduce VELCADE to 1 mg/m2

Grade 2 with pain or Grade 3 (severe symptoms; limiting self care ADL ‡)

 

Withhold VELCADE therapy until toxicity resolves. When toxicity resolves reinitiate with a reduced dose of VELCADE at 0.7 mg/m2 once per week.

Grade 4 (life-threatening consequences; urgent intervention indicated)

 

Discontinue VELCADE

2.6 Dosage in Patients with Hepatic Impairment

Patients with mild hepatic impairment do not require a starting dose adjustment and should be treated per the recommended VELCADE dose. Patients with moderate or severe hepatic impairment should be started on VELCADE at a reduced dose of 0.7 mg/m2 per injection during the first cycle, and a subsequent dose escalation to 1.0 mg/m2 or further dose reduction to 0.5 mg/m2 may be considered based on patient tolerance (see Table 4) [see Use in Specific Populations (8.7)and Clinical Pharmacology (12.3)].

Table 4: Recommended Starting Dose Modification for VELCADE in Patients with Hepatic Impairment

 

Bilirubin Level

SGOT (AST) Levels

Modification of Starting Dose

Abbreviations: SGOT = serum glutamic oxaloacetic transaminase; 
AST = aspartate aminotransferase; ULN = upper limit of the normal range.

Mild

Less than or equal to 1.0x ULN

More than ULN

None

More than 1.0x–1.5x ULN

Any

None

Moderate

More than 1.5x–3x ULN

Any

Reduce VELCADE to 0.7 mg/m2 in the first cycle. Consider dose escalation to 1.0 mg/m2 or further dose reduction to 0.5 mg/m2 in subsequent cycles based on patient tolerability.

Severe

More than 3x ULN

Any

2.7 Administration Precautions

The drug quantity contained in one vial (3.5 mg) may exceed the usual dose required. Caution should be used in calculating the dose to prevent overdose [see Dosage and Administration (2.8)].

When administered subcutaneously, sites for each injection (thigh or abdomen) should be rotated. New injections should be given at least one inch from an old site and never into areas where the site is tender, bruised, erythematous, or indurated.

If local injection site reactions occur following VELCADE administration subcutaneously, a less concentrated VELCADE solution (1 mg/mL instead of 2.5 mg/mL) may be administered subcutaneously [see Dosage and Administration (2.8)]. Alternatively, the intravenous route of administration should be considered [see Dosage and Administration (2.8)].

VELCADE is an antineoplastic. Procedures for proper handling and disposal should be considered [see How Supplied/Storage and Handling (16)].

2.8 Reconstitution/Preparation for Intravenous and Subcutaneous Administration

Proper aseptic technique should be used. Reconstitute only with 0.9% sodium chloride. The reconstituted product should be a clear and colorless solution.

Different volumes of 0.9% sodium chloride are used to reconstitute the product for the different routes of administration. The reconstituted concentration of bortezomib for subcutaneous administration (2.5 mg/mL) is greater than the reconstituted concentration of bortezomib for intravenous administration (1 mg/mL). Because each route of administration has a different reconstituted concentration, caution should be used when calculating the volume to be administered [see Dosage and Administration (2.7)].

For each 3.5 mg single-use vial of bortezomib reconstitute with the following volume of 0.9% sodium chloride based on route of administration (Table 5):

Table 5: Reconstitution Volumes and Final Concentration for Intravenous and Subcutaneous Administration

Route of administration

Bortezomib
(mg/vial)

Diluent
(0.9% Sodium Chloride)

Final Bortezomib concentration (mg/mL)

Intravenous

3.5 mg

3.5 mL

1 mg/mL

Subcutaneous

3.5 mg

1.4 mL

2.5 mg/mL

Dose must be individualized to prevent overdosage. After determining patient body surface area (BSA) in square meters, use the following equations to calculate the total volume (mL) of reconstituted VELCADE to be administered:

  • Intravenous Administration [1 mg/mL concentration]

Figure

  • Subcutaneous Administration [2.5 mg/mL concentration]

Figure

Stickers that indicate the route of administration are provided with each VELCADE vial. These stickers should be placed directly on the syringe of VELCADE once VELCADE is prepared to help alert practitioners of the correct route of administration for VELCADE.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. If any discoloration or particulate matter is observed, the reconstituted product should not be used.

Stability: Unopened vials of VELCADE are stable until the date indicated on the package when stored in the original package protected from light.

VELCADE contains no antimicrobial preservative. Reconstituted VELCADE should be administered within 8 hours of preparation. When reconstituted as directed, VELCADE may be stored at 25°C (77°F). The reconstituted material may be stored in the original vial and/or the syringe prior to administration. The product may be stored for up to 8 hours in a syringe; however, total storage time for the reconstituted material must not exceed 8 hours when exposed to normal indoor lighting.

3 DOSAGE FORMS AND STRENGTHS

Each single-use vial of VELCADE contains 3.5 mg of bortezomib as a sterile lyophilized white to off-white powder.

4 CONTRAINDICATIONS

VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol. Reactions have included anaphylactic reactions [see Adverse Reactions (6.1)].

VELCADE is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of VELCADE.

5 WARNINGS AND PRECAUTIONS

5.1 Peripheral Neuropathy

VELCADE treatment causes a peripheral neuropathy that is predominantly sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥ Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous versus intravenous the incidence of Grade ≥ 2 peripheral neuropathy was 24% for subcutaneous and 39% for intravenous. Grade ≥ 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.

Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may require a decrease in the dose and/or a less dose-intense schedule [see Dosage and Administration (2.5)]. In the VELCADE versus dexamethasone phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥ Grade 2 peripheral neuropathy following dose adjustment or interruption. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥ Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies [see Adverse Reactions (6.1)]. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

5.2 Hypotension

The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics [see Adverse Reactions (6.1)].

5.3 Cardiac Toxicity

Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during VELCADE therapy, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE versus dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the VELCADE and dexamethasone groups, respectively. The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤ 1% for each individual reaction in the VELCADE group. In the dexamethasone group the incidence was ≤ 1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

5.4 Pulmonary Toxicity

Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration have occurred in patients receiving VELCADE. Some of these events have been fatal.

In a clinical trial, the first two patients given high-dose cytarabine (2g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy.

There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease.

In the event of new or worsening cardiopulmonary symptoms, consider interrupting VELCADE until a prompt and comprehensive diagnostic evaluation is conducted.

5.5 Posterior Reversible Encephalopathy Syndrome (PRES)

Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving VELCADE. PRES is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing PRES, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing PRES is not known.

5.6 Gastrointestinal Toxicity

VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting [see Adverse Reactions (6.1)] sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Interrupt VELCADE for severe symptoms.

5.7 Thrombocytopenia/Neutropenia

VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia related to pretreatment platelet count is shown in Table 6. In the relapsed multiple myeloma study of VELCADE versus dexamethasone, the incidence of bleeding (≥ Grade 3) was 2% on the VELCADE arm and was < 1% in the dexamethasone arm. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Platelet count should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE [see Table 2 and Dosage and Administration (2.4)]. Gastrointestinal and intracerebral hemorrhage has been reported in association with VELCADE. Transfusions may be considered.

Table 6: Severity of Thrombocytopenia Related to Pretreatment Platelet Count in the Relapsed Multiple Myeloma Study of VELCADE versus Dexamethasone

Pretreatment
Platelet Count*

Number of Patients
(N=331)†

Number (%) of Patients
with Platelet Count 
< 10,000/µL

Number (%) of Patients
with Platelet Count 
10,000-25,000/µL

 * A baseline platelet count of 50,000/µL was required for study eligibility

† Data were missing at baseline for 1 patient

≥ 75,000/µL

309

8 (3%)

36 (12%)

≥ 50,000/µL-< 75,000/µL

14

2 (14%)

11 (79%)

≥ 10,000/µL-< 50,000/µL

7

1 (14%)

5 (71%)

5.8 Tumor Lysis Syndrome

Tumor lysis syndrome has been reported with VELCADE therapy. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. Monitor patients closely and take appropriate precautions.

5.9 Hepatic Toxicity

Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt VELCADE therapy to assess reversibility. There is limited re-challenge information in these patients.

5.10 Embryo-fetal Risk

Women of reproductive potential should avoid becoming pregnant while bei

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Velcade 3.5 Mg 1 Vial

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